In-line control of the lyophilization process. A gentle PAT approach using software sensors

A lyophilization process is usually only specified in terms of a ‘recipe’ (shelf temperature and chamber pressure vs. time); according to the recent PAT guidelines issued by FDA, there is the need to develop in-line tools to enable better monitoring and control freeze-drying. In this work an advanced Manometric Temperature Measurement approach, called DPE (Dynamic Parameters Estimation) is first presented, based on a detailed mathematical model. In alternative, the “smart vial” concept is proposed, a Kalman filter based observer allowing an almost continuous monitoring without probes physically inserted into the product. Results obtained for pharmaceutical products in vial in a small industrial prototype equipped with the DPE-based LyoDriver control software, are presented. The software is capable to determine the optimal shelf temperature for primary drying, ensuring the fastest drying time without overcoming the maximum allowable product temperature both in scouting and production cycles. Finally, the two complementary monitoring systems, the DPE and the “smart vial”, are combined in an even more robust hybrid control system.